Jin Zhe, Hammoud Hayma, Bhandage Amol K, Koreli Stasini, Chowdhury Azazul Islam, Bergsten Peter, Birnir Bryndis
Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Front Immunol. 2025 Jun 17;16:1576216. doi: 10.3389/fimmu.2025.1576216. eCollection 2025.
Glucose uptake in activated CD4 T cells is essential for increased metabolic needs, synthesis of biomolecules and proliferation. Although, facilitated glucose transport is the predominant route for glucose entry at the time of activation, here we demonstrate role for the sodium-dependent glucose transporter SGLT2. By 72 h after activation, SGLT2 is expressed and functional in the human CD4 T cells. SGLT2 inhibitors, phlorizin and empagliflozin decreased glucose uptake into the human CD4 T cells compared to untreated cells. Phlorizin (25 μmol/L) reduced glycolysis at 5.6 mmol/L glucose and IFNγ levels at both 5.6 mmol/L and 16.7 mmol/L glucose. In contrast, empagliflozin (0.5 μmol/L) only decreased IFNγ levels in 16.7 mmol/L glucose. GABA enhanced phlorizin inhibition at both 5.6 mmol/L and 16.7 mmol/L glucose in the presence of insulin. Insulin strengthens GABA receptors signaling in CD4 T cells. The results are consistent with expression of SGLT2 after activation of human CD4 T cells, that facilitates concentrating glucose uptake into the cells, enabling enhanced release of inflammatory molecules like IFNγ. Importantly, inhibition of SGLT2 decreases IFNγ release.
活化的CD4 T细胞摄取葡萄糖对于满足增加的代谢需求、生物分子合成和细胞增殖至关重要。虽然在活化时易化葡萄糖转运是葡萄糖进入细胞的主要途径，但我们在此证明了钠依赖性葡萄糖转运体SGLT2的作用。活化后72小时，SGLT2在人CD4 T细胞中表达并发挥功能。与未处理的细胞相比，SGLT2抑制剂根皮素和恩格列净降低了人CD4 T细胞对葡萄糖的摄取。根皮素（25 μmol/L）在葡萄糖浓度为5.6 mmol/L时降低糖酵解，在葡萄糖浓度为5.6 mmol/L和16.7 mmol/L时降低IFNγ水平。相比之下，恩格列净（0.5 μmol/L）仅在葡萄糖浓度为16.7 mmol/L时降低IFNγ水平。在存在胰岛素的情况下，γ-氨基丁酸（GABA）增强了根皮素在葡萄糖浓度为5.6 mmol/L和16.7 mmol/L时的抑制作用。胰岛素增强了CD4 T细胞中GABA受体的信号传导。这些结果与人CD4 T细胞活化后SGLT2的表达一致，SGLT2有助于将葡萄糖浓缩摄取到细胞中，从而增强IFNγ等炎症分子的释放。重要的是，抑制SGLT2可减少IFNγ的释放。
